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Alcoholic Cardiomyopathy: The Underlying Metabolic Changes
'Cardiomyopathy Introduction' Like any other muscle, cardiac muscle requires energy in order to contract, which ultimately leads to the systemic circulation of blood within the body. The majority of ATP utilized in cardiac muscle is produced via the breakdown of fatty acids. Various primary articles have observed that cardiomyopathy, the deterioration of the muscle functionality within the heart, can be associated with alcoholism. This learning module will focus on numerous primary articles that have contributed to understanding the effects of alcohol abuse to cardiomyopathy. An emphasis will be put towards the underlying metabolic changes within myocardium that are associated with chronic alcohol consumption. Through an analysis of several primary articles we will attempt to answer: What metabolic processes within myocardium are affected by chronic alcohol consumption? How are these changes in metabolic processes implicated in the development of cardiomyopathy? Cardiomyopathy describes a group of diseases related to heart muscle, which leads to the weakening of heart muscle and can develop into life-threatening complications (Sankaranarayanan, 2010). The causes for the structural and functional abnormalities of cardiomyopathy are independent of coronary artery disease, hypertension or valvular disease (Sankaranarayanan, 2010). Cardiomyopathy is categorized based on the morphological characteristics of the disease (Sankaranarayanan, 2010). Dilated cardiomyopathy is characterized by a decrease in ejection fraction, the volumetric fraction of blood pumped out of the ventricle with each heartbeat, and an increase in left ventricular size (Sankaranarayanan, 2010). Dilated cardiomyopathy can lead to heart failure and possibly stroke if not treated due to the thickening and stiffening of the heart muscle, which may lead to the inability to sufficiently pump blood from the heart (Sankaranarayanan, 2010). Other symptoms that have been linked with cardiomyopathy include swelling of the legs, fatigue, irregular heartbeats and breathlessness with exertion (Mayo Clinic, 2012). You are encouraged to complete the self-assessment quiz after reading through this module in order to gauge your knowledge of cardiomyopathy. 'Alcoholic Cardiomyopathy Introduction' Notwithstanding similar physiological manifestations, the causes of cardiomyopathy range from genetic heart defects to metabolic disorders to an excess of toxins in the heart tissue. We will specifically examine the metabolic changes and symptoms associated with alcoholic cardiomyopathy, a disease that results from chronic excess alcohol intake. Alcoholic cardiomyopathy is a type of dilated cardiomyopathy, sharing many of the same symptoms typically associated with dilated cardiomyopathy. Alcoholic cardiomyopathy can be treated with Beta blockers and diuretics to improve heart function; however, complete abstinence from alcohol remains the only way to reverse the heart damage. This lack of a dedicated treatment means that alcohol cardiomyopathy remains a promising target for study in order to hopefully develop such a treatment in the future. Ultimately, despite the similarities that alcoholic cardiomyopathy shares with many other types of cardiomyopathy, the metabolic processes that cause the symptoms and heart failure previously described are significantly different than the causes in other cardiomyopathies. 'Acetaldehyde decreases cardiac protein synthesis' 'Protein Synthesis Inhibition' Accumulation of triglycerides and the decreased extraction of fatty acids have been implicated as the causes of alcoholic cardiomyopathy (Schreiber et al., 1974). Previous studies have determined that alcohol-derived metabolites, such as acetaldehyde, may also be connected. Guinea pig hearts perfused with 0.8 mM acetaldehyde displayed strong inhibition of cardiac protein synthesis. In order to determine whether or not protein synthesis inhibition is related the effects of acetaldehyde on contractile function, Schreiber et al. isolated cardiac proteins in heart muscle microsomes perfused with various concentration of acetaldehyde as cell free systems. The inhibition effects of lower acetaldehyde concentrations, simulating immediate alcohol consumption, are also investigated. 'Methods' Cardiac muscle protein synthesis was evaluated by the ability of microsomes obtained from heart tissue in a cell free system to incorporate labelled amino acids into protein, with and without acetaldehyde. Guinea pigs ages 3-4 weeks were used in this study, whereby their heart is removed and the left ventricle homogenized. Isolated microsomes with proteins were submerged in standard cell free solution complete with energy metabolism substrates/enzymes as well as amino acids. 14C-Leucine was used as the amino acid tracer to quantify total tagged protein presence. Samples were incubated at final acetaldehyde concentrations of 0 mM, 3 mM, 6 mM and 12 mM. Perfusion studies were performed on heart tissue using perfusate laced with 14C-Lysine and 0.2 mM acetaldehyde, with the experiment lasting 5 hours. After of which the left ventricle was purified using previously mentioned protocol and protein synthesis quantified as µmol 14C-Lysine/g protein in the left ventricle. 'Effects of Acetaldehyde on the Guinea Pig Heart' It has been previously reported that 200 mg/100 mL of ethanol, while sufficient in decreasing kidney albumin synthesis, does not in any way affect cardiac function or cardiac protein synthesis (Schreiber et al., 1974). However, cases of chronic alcoholism resulting in cardiomyopathy are well known. Acetaldehyde, an ethanol metabolite whose presence increases dramatically post alcohol consumption, produces a significant decrease in cardiac protein synthesis as well abnormally stimulating the heart rate (chronotropic effects) and heart beat (inotropic effects). These contractility effects are directly linked to heart muscle condition which, through chronic stimulation, may develop cardiomyopathy (Schreiber et al., 1974). At acetaldehyde concentrations of 0.12 mM, protein synthesis in isolated microsomes was decreased to 52% of the 0 mM acetaldehyde controls (P < 0.001). While moderate levels of 0.03 mM – 0.06 mM acetaldehyde concentrations decreased protein synthesis to 65% of the controls (P < 0.01). Since acetaldehyde levels post alcohol consumption has been reported between the ranges of 0.03 mM to 0.3 mM, it is more than possible that the decreased protein synthesis in the heart due to acetaldehyde contributes to cardiomyopathy independent of contractility effects. In the perfusion studies, the guinea pig heart has been shown to be extremely vulnerable to cardiac disruptions. Decreased coronary flow resulted in complete asystole failure in 10 – 15 minutes. In 12 perfusion experiments, protein synthesis in the control displayed 37.5 +- 2.1 µmol lysine/g protein after 5 hours of perfusion. Meanwhile, 0.2 mM acetaldehyde perfusion produced only 28.3 +- 2.4 µmol lysine/g protein, a 25% decrease (P < 0.05). 'Alcohol influence on Myocardial Enzyme Activity and Myocardial Function ' Alcoholic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM) has been reported to exhibit no histopathological or clinical difference (Hibbs et al., 1965; Olsen, 1975). The causal relationship between alcohol and DCM has also been demonstrated (Richardson, Wodak, Atkinson, Saunders, & Jewitt, 1986), thus ACM is considered a type of DCM (Iacovoni, De Maria, & Gavazzi, 2010). Richardson et al (1986) demonstrated the relationship between alcohol intake and DCM by assessing patients with DCM and relate their myocardial enzyme activities and myocardial function to the influence of alcohol. Myocardial biopsy was performed to assay various enzymes including creatine kinase, lactate dehydrogenase, malic dehydrogenase, and aspartate aminotransferase. There were significant correlations between myocardial enzyme activities and cumulative lifetime alcohol consumption, maximum daily intake, and recent daily intake (Figure 2 and 3). Tissue enzyme activities, except for aspartate aminotransferase, were significantly higher in the heavy drinking group compared with the abstaining or light drinking group (Figure 2). The pathophysiological mechanisms underlying ACM are poorly understood, where different mechanisms are suggested, including direct toxic myocyte damage (Chen, Wang, & Wang, 2000), structural changes in the contractile proteins, intracellular organelle dysfunction (Fernandez-Sola et al., 2007) and alterations in calcium homeostasis (Alexander, 1967). Animal models need to be evaluated carefully as alcohol associations such as left-ventricular myocyte loss is demonstrated partially in animal models (Hibbs et al., 1965). A Transgenic Model of Acetaldehyde Overproduction Accelerates Alcohol Cardiomyopathy 'Modelling chronic alcoholism with transgenic mice' Based on a number of studies modelling alcoholic cardiomyopathy in animals, one very important contributor to the negative health effects associated with alcoholic cardiomyopathy is acetaldehyde, which is also the main metabolite of ethanol. Liang et al. tested this hypothesis by developing transgenic mice with a MyADH transgene to test how a greater capacity to metabolize ethanol into acetaldehyde, producing a greater concentration of acetaldehyde in a short period of time, would influence the structure and function of the heart tissue. Multiple trangenic lines were ultimately produced, and the ADH activity of these mice was measured using assays that used the conversion of NAD+ to NADH in the presence of ethanol as an indicator of ADH activity (Liang et al.,1999). These assays showed that these transgenic lines had as much as 40 times the ADH activity of the basic FVB line of mice (see figure 4). One line in particular, line 239, was chosen for use in all further tests. These mice had similar physical characteristics as the normal FVB mice, such as fertility and body weight, but a novel subcutaneous sampling method showed that the cardiac acetaldehyde concentration in the transgenic mice was four times greater than the base FVB mice following 3g/kg ethanol injections (Liang et al.,1999). This suggests that the increased ADH activity in these transgenic mice led to a similar increase in the ability of these mice to metabolize ethanol into acetaldehyde. 'Cardiomyopathy markers' After ensuring that the model accurately represented the conditions brought on by chronic alcohol intake, the effects of a chronic 4% ethanol diet were tested over a period of 5 months. Northern blots were used to measure the mRNA levels of SkActin and ANF, which are proteins that have been previously shown to be sensitive indicators of cardiac damage, and statistically significant increases in both of these proteins were observed in the transgenic mice on an alcohol diet (see figure 6)(Liang et al.,1999). 'Heart enlargement' Another common feature of human cardiomyopathies that was measured was heart enlargement, and this was done by simply measuring the mass of the hearts of the mice relative to their total body mass. Ultimately, a statistically significant difference in mass was seen between FVB mice on an ethanol diet and FVB mice on an ethanol-free diet, as well as between transgenic mice on an ethanol diet and FVB mice on ethanol diet (see figure 7) (Liang et al.,1999). This suggests that, while an ethanol diet itself results in an enlarged heart, the chronic ethanol diet modelled by the transgenic mice further magnifies this enlargement. Morphological changes from alcoholic cardiomyopathy Finally, morphological effects of the alcohol diet on both FVB mice and transgenic ADH mice were determined using electron microscopy to observe the morphology of the cardiac tissue of these mice. Many significant morphological changes, such as intracellular edema, glycogen accumulation, fragmentation, focal lesions, and loss of myofibrils, were observed in both alcohol treated groups, with a more significant loss of myofibrils and an increase in edematous sarcoplasm specifically in transgenic mice (see figure 8) (Liang et al.,1999). These are morphological changes that are frequently seen in human cardiomyopathies; however, there was no significant change in lipid inclusions in any mice, even though lipid inclusions are another common element of human cardiomyopathies. Lastly, a decrease in contractility, another significant symptom of human cardiomyopathies, was also observed between both the FVB alcohol treated group and FVB control group, as well as between the transgenic ADH alcohol group and the transgenic ADH control group (see figure 9) (Liang et al.,1999). Summary Ultimately, in transgenic mice produced to model chronic alcohol abuse in humans, the highly elevated levels of acetaldehyde resulted in elevated levels of many markers that typically indicate human cardiomyopathies as well as many morphological changes consistent with human alcohol-induced cardiomyopathy. This supports the hypothesis that acetaldehyde is an important element with respect to the cardiac damage caused by chronic alcohol-induced cardiomyopathy. 'Myocardial Function and Lipid Metabolism in the Chronic Alcoholic Animal' 'Myocardial Abnormalities in Alcoholic Animals ' Chronic alcohol intake has been studied in its effects to bring about cardiomyopathy in animals. Consumption of large quantities has been linked to damage of the myocardial muscle tissue in its function to constrict and dilate the heart. Metabolic abnormalities have also been studied postmortem in subjects. This study utilized an animal model, the mongrel dog, to understand the effects of chronic alcohol intake on the myocardial tissue. The study was designed so as to use a suitable model to obtain results which could be comparable when studying the human physiological effects of chronic alcohol intake (Regan et al., 1974). Mongrel dogs of 2-3 years of the male sex were divided into a control and experimental group. The control group was given a diet consisting of 26% protein, 12% fat, and 62% carbohydrate. The experimental group was given a diet consisting of 16.6% protein, 7.7% fat, 39.7% carbohydrate and 36% ethanol 6 days a week with the diet on the seventh day the same as the control group. The caloric content remained constant for the two groups for 20 months. The qualitative measurements and analysis consisted of venous blood samples for determination of plasma lipids, hemodynamic studies to assess ventricular function, and metabolic studies to determine intake of lipids (Regan et al., 1974). In the comparison of the control group to the experimental group, it was found that the weight gain, hematocrit, serum protein and blood glucose levels remained constant. Trace element studies on the blood plasma revealed that vitamin and mineral levels between the control and the experiment groups remained unchanged (Regan et al., 1974). 'Hemodynamic Status' Hemodynamic studies related to the blood flow and motion rates were performed to establish a comparison between the control group and experimental group. It was noted that there was a higher end-diastolic pressure while the end-diastolic volume was lower in the left ventricle. Stiffness of the ventricle was tested using infusion rates of saline injections. It was noted that there was a significant increase in end-diastolic pressure in the alcohol diet group when comparing with the control group (Regan et al., 1974). 'Metabolic Status' Myocardial metabolism of radiolabeled oleic acid was compared between the control and experimental group. In comparison to this, the uptake of the fatty acid was studied along with the CO2 release. These parameters were also studied in relation to hemodynamic changes to test whether it had any effect on the metabolism of the fatty acids. It was noted that there was a decrease in uptake and metabolism of the oleic acid in the experimental group compared to the control (Figure 10). Specifically the triglyceride uptake of the experiemental group was signficantly decreased while the fatty acid and cholestrol concentrations remained constant (Regan et al., 1974). 'Conclusions and Future Directions' The study focused on changes occurring in nutrition, hemodynamics and metabolism when comparing mongrel dogs on a normal diet to chronic alcohol diet-based dogs. The major findings indicated that in terms of nutritional status the weight of the dogs along with plasma elements remained constant between the two groups. The hemodynamic findings reported a significant increase in end-diastolic pressure in the experimental animals supporting previous studies indicating an increased stiffness in the myocardial muscle. The metabolic studies showed decreased intake of triglycerides in the experimental group along with decreased CO2 production which was interpreted as reduced oxidation in the cells as a result of the reduced activity of the rate-limiting enzymes in the citric acid cycle (Regan et al., 1974). The findings of this study have revealed clear and concise effects on the myocardial muscle in terms of hemodynamic activity and metabolism in a case where a dog was subject to chronic alcoholism. Further studies have confirmed similar effects on human myocardial muscle when subject to alcoholism. It remains to be tested whether the alteration of lipid metabolism was a direct result of alcoholism or whether genetics and cation gradients in the muscle played any role (Regan et al., 1974). 'Chronic ethanol consumption increases cardiomyocte fatty acid uptake ' 'Utilizing an Animal Model for Alcoholic Cardiomyopathy' Alcohol is a major cause of human cardiomyopathy and decreased cardiac output, yet there are not many available wild-type animal models of the underlying metabolic processes that are affected by chronic alcohol consumption (Hu et al., 2013). Hu et al. attempted to recreate an animal model of human cardiomyopathy using wild type male C57BL/6J mice. Through utilizing this animal model, this group observed novel findings about the metabolic effects to myocardium due to alcohol consumption. We will review the methods and results of this work, and review how it fits into the greater picture of alcoholic cardiomyopathy. 'Long Chain Fatty Acids' A key energy source for cardiomyocytes is long chain fatty acids (LCFA), which are transported to the muscle tissue of the heart and metabolized via β-oxidation within mitochondria (Hu et al., 2013). In addition to being a source of energy, LCFA can also be esterified to triglycerides (TG) as a form of energy storage. Hu et al. observed anincreased LCFA uptake in mice that were fed a high alcohol content diet. Increased myocardial TG accumulation in wildtype mice may explain the decreased cardiac function that is associated with chronic alcoholic consumption. 'Methods' The study utilized 4 mice groups, a control group, a 10% (v/v), 14% (v/v) and 18% (v/v) EtOH groups, where EtOH was provided in the drinking water for 12 weeks. Following the EtOH feeding period the mice were sacrificed and cardiac tissue and blood were harvested in order to be analyzed. Lipid analysis was utilized to study the cardiac content of selected lipids, while cardiac ATP assays were used to measure the ATP concentration of the cardiac tissue removed immediately after sacrifice. Cardiac function was measured using 2D echocardiography on mice that were put to sleep (Hu et al., 2013). 'Chronic Alcohol Intake Increased LCFA Uptake & Downregulated Oxidative Phosphorylation Genes' As observed in previous studies, increased alcohol intake was associated with worse cardiac function in all groups, as measured by ejection fraction, the volumetric fraction of blood pumped out of the ventricle with each heart beat (see figure 11).These are consistent with the literature that chronic alcoholism leads to poorer cardiac function. The cause of this relatively worse cardiac functioning is not fully understood, but the observation of lipid droplets in the alcohol groups may provide an interesting direction to look towards (Hu et al., 2013). The hearts of the EtOH groups exhibited accumulation of lipids within the myocardia, which was observed as small droplets in stained tissue (see figure 12). Hu et al. observed that these droplets were in direct contact with mitochondria. Lending more evidence towards increased fat content within the alcohol fed groups was the observance of significant increases in LCFA uptake, as evidenced by the increased concentration of the free fatty acid, oleic acid (see figure 13). These obser vations suggest that fatty acid uptake may be implicated in reduced cardio functioning. Hu et al. analyzed the expression of LCFA transport proteins and observed an increase in two vital transporters, CD36 and Slc27aI. Furthermore other genes that were up regulated included those involved in the de-novo synthesis of fatty acids, while lipoprotein lipase which catalyzes the hydrolysis of triglycerides was unchanged in its expression(Hu et al., 2013). The increased expression of these key genes suggests that an increase in alcohol consumption can have a significant effect not only on the uptake of LCFA into myocardia and its esterification to triglycerides, but also on the pathways responsible for the synthesis of fatty acids within the heart. In addition to an increased expression in fatty acid transporters, the study observed down regulation of various oxidative phosphorylation pathway genes in the alcohol fed group. Genes corresponding to the various components of the electron transport chain, such as Complex I, II, III, IV of the electron transport chain were all significantly down regulated in the alcohol groups, suggesting a decrease in oxidative phosphorylation capability of myocardium (Hu et al., 2013). The decrease in oxidative phosphorylation capability led to a 30% decrease in ATP content in the highest alcohol fed group when compared to the control group (see figure 14). This may be explain the decreased cardiac function in these groups, as they may not have sufficient energy in order to contract the heart muscles. 'Conclusions and Future Directions' The paper notes that the processes by which lipid accumulation via increase LCFA uptake can lead to myocardial dysfunction still remains to be determined, but the effective upregulation of genes responsible for transporting fatty acids, and the de novo synthesis of LCFA play a role in the relationship between EtOH consumption and increased fat content of myocardia tissue (Hu et al., 2013). It is suggested that the accumulation of TG within myocardia may be a marker of the accumulation of more toxic lipid derivatives, which play a further role in the decreased cardiac function of alcoholics. Furthermore these toxic lipids may be what lead to the down-regulation of key oxidative enzymes, which ultimately leads to a decrease in myocardial ATP content and functionality. However, it is not entirely clear if decreased expression of oxidative enzymes is the result of myocardial injury due to EtOH and it metabolites, or if it is due to the increase in lipid accumulation (Hu et al., 2013). Ultimately this paper illustrates that a possible connection between EtOH consumption, fatty acid uptake within the heart and the downregulation of oxidative phosphorylation within the heart. How these pieces exactly fit together still needs to be further studied, but Hu et al. have published some novel findings of these interactions, and have shown that a wild type mice model can be utilized effectively when studying alcoholic cardiomyopathy. 'Conclusions and Summary of Primary Data' This learning module has covered several areas of alcoholic cardiomyopathy that has focused on different proposed mechanisms, both in the metabolic pathways of myocardia and other biochemical pathways. We have attempted to provide a more comprehensive look at this field by covering various areas. We will now present a conclusion and summary of the primary data that has been discussed in this module, and how it answers our research question: What metabolic processes within myocardium are affected by chronic alcohol consumption? How are these changes in metabolic processes implicated in the development of cardiomyopathy? 'Functional and Structural Changes' A recurring conclusion among the papers we have presented is the observation that chronic alcohol consumption does lead to both structural and functional changes within the heart. This was particularly evident in Liang et al.’s work that indicated an increase in heart size for mice that were able to overproduce acetaldehyde, the main metabolite of ethanol. Furthermore Hu et al. observed a decrease in ejection fraction among wild-type mice that were fed a high ethanol diet, lending further evidence that alcohol consumption shows a measurable effect on cardiac function. The hemodynamic status of mongrel dogs that were given a high ethanol diet showed stiffness of the ventricle and higher diastolic pressure. 'Acetaldehyde' Acetaldehyde was implicated in more than one paper we reviewed, and its role in cardiomyopathy cannot be understated. Its effects are wide ranging with respects to myocardium, such as inhibiting cardiac protein synthesis (Schreiber et al., 1974), which resulted in reduced coronary flow in guinea pigs. Furthermore, acetaldehyde’s role in cardiomyopathy development was indicated in Liang et al.’s study, which looked at cardiomyopathy symptoms in mice that had been genetically modified in order to metabolize ethanol to acetaldehyde at a greater rate. The metabolism of ethanol to acetaldehyde undoubtedly plays a large role in the development of cardiomyopathy. 'Metabolism' 'The various underlying metabolic changes proposed in these studies consistently showed that the underlying cause of cardiomyopathy stems from metabolic changes within myocardium. Whereas functional and structural changes are a consequence of cardiomyopathy, and acetaldehyde is the primary alcohol metabolite that is implicated in the observed changes within myocardia, it is the metabolic changes observed that are the underlying cause for the development of the disease. Varying metabolic and enzymatic changes were observed, such as increase in creatine kinase activity being correlated with alcohol intake in humans (Richardson et al., 1986). This is suggestive of an increase in ATP utilization in the hearts of heavy drinkers. The animal model of the mongrel dog illustrated a decrease in myocardial uptake of triglycerides, while fatty acid metabolism and oxidative phosphorylation were reduced in the cells (Regan et al., 1974). Hu et al.’s work with wild-type mice fed a high alcohol diet seemed to contradict the work with mongrel dogs, as fatty acid uptake was observed to be much higher in wild-type C57BL mice compared to control. Similarly to mongrel dogs, C57BL mice showed a decrease in oxidative phosphorylation capacity due to the downregulation of key ETC enzymes, ultimately leading to a decrease in ATP concentration within myocardia. Ultimately the effects on metabolic pathways involved in alcoholic cardiomyopathy are complex and numerous. This review of just a few articles from this broad field has yielded numerous observed metabolic changes, such as an increase in fatty acid uptake and a decrease in oxidative phosphorylation. Cardiomyopathy may not be able to be pinned to any one single metabolic pathway or disorder, but the important work and studies completed thus far have shown fairly conclusive evidence that chronic alcohol consumption can lead to these metabolic changes, which may ultimately manifest in the form of potentially fatal cardiomyopathy. 'Public Health Impact & Education ' Chronic consumption of alcohol, without a doubt, impacts the heart negatively and may eventually bring about cardiomyopathy. The various studies detailed above provides surmounting evidence that, whether through metabolic changes or protein synthesis inhibition, alcohol leads to irregular chronotropic and inotropic effects in the heart. These irregularities will persist, given sufficient and regular consumption, eventually resulting in cardiomyopathy. Depending on the severity of the situation, the condition may prove fatal. The Heart and Stroke Foundation has already named alcohol as one of the primary factors of heart disease. However, while alcohol-induced hepatic damage is well known in society, its relation to heart damage is much more obscure. Thus, it is important to create awareness of this issue, as well as chronic overconusmption and the consequences thereof. It has been found that chronic overconsumption of alcohol is the result of consuming approximately 36% of the daily caloric intake as alcohol. Awareness to this issue is the first step in prevention of cardiomyopathy due to chronic alcoholism. Further publicizing for this issue is required in terms of the mental health aspect of chronic alcoholism for effective prevention. Self-Assessment Questions The following self-assessment questions will test the knowledge you have hopefully acquired during this learning module. You are encouraged to attempt the self-assessment without referring back to the module, and then compare you answers with the answer section. 1. Alcohol-fed C57BL mice exhibited: ' A. Decreased myocardial lipid content B. Decreased expression of key oxidative phosphorylation genes C. Increased myocardial ATP levels D. A & C '''2. Ejection fraction: ' A. Is a measure of the volumetric fraction of blood pumped out of the ventricle with each heartbeat B. Was increased in alcohol-fed C57BL mice C. Is a measurement of cardiac function D. Both A & C '3. Oleic acid: ' A. Uptake was observed to increase in alcohol-fed mice B. Is an unsaturated molecule C. Is an example of a triglyceride D. Both A & B '''4. Name three genes/proteins whose expression was measured to be affected by chronic alcohol consumption. Was the gene upregulated, downregulated or unchanged? What is it's function with respects to cardiomyopathy? 5. Protein marker(s) used to ensure that the conditions modelled alcoholic cardiomyopathy were: A. SkActin B. ADH C. NADH D. ANF E. A and D 6. List 3 morphological changes associated with alcoholic cardiomyopathy. 7. The properties of the transgenic mice included: A. Increased ADH activity B. Increased body weight C. Decreased fertility D. Both A and C E. All of the above Self-Assessment Answers 1. Alcohol-fed C57BL mice exhibited: A. Decreased myocardial lipid content- Alcohol-fed mice showed an increased in both fatty acid uptake, and lipid content of the heart tissue B. Decreased expression of key oxidative phosphorylation genes- Genes corresponding to various components of the electron transport chain were downregulated in the alcohol fed group C. Increased myocardial ATP levels- Due to the downregulation of ETC genes, there was a significant decrease in ATP levels for the alcohol-fed groups. D. A & C 2. Ejection fraction: A. Is a measure of the volumetric fraction of blood pumped out of the ventricle with each heartbeat B. Was increased in alcohol-fed C57BL mice- Ejection fraction was decreased in alcohol-fed mice, indicative of poorer cardiac functioning C. Is a measurement of cardiac function- 'Ejection fraction was one of two cardiac functioning measurements '''D. Both A & C ' '''3. Oleic acid: A. Uptake was observed to increase in alcohol-fed mice- '''See figure '''B. Is an unsaturated molecule – '''Oleic acid is an monounsaturated long chain fatty acid C. Is an example of a triglyceride- this is false, oleic acid is an unsaturated fatty acid '''D. Both A & B 4. Name three genes/proteins whose expression was measured to be affected by chronic alcohol consumption. Was the gene upregulated, downregulated or unchanged? What is its function with respects to cardiomyopathy? *Note there are more correct answers The CD36 gene is upregulated in alcohol-fed groups. The CD36 gene corresponds to a vital LCFA transport protein found in myocardia. Its upregulated expression results in the increased uptake of LCFA in myocardia, which ultimately leads to an increase in fatty acid content within the heart. Lipoprotein lipase is the enzyme, which is responsible for the hydrolysis of triglycerides. Its expression is unchanged in the alcohol-fed mice group, suggesting that the increased LCFA uptake of the heart does not result in an increase in hydrolysis of TG. Genes corresponding to various components of the ETC are downregulated in alcohol-fed groups. This ultimately leads to a decrease in ATP concentration within the myocardia of alcohol-fed mice, which may explain the decreased cardiac functioning of these mice, due to the fact that ATP is in shorter supply. 5. Protein marker(s) used to ensure that the conditions modelled alcoholic cardiomyopathy were: A. SkActin B. ADH C. NADH D. ANF E. A and D 6. List 3 morphological changes associated with alcoholic cardiomyopathy - intracellular edema - glycogen accumulation - fragmentation - focal lesions - loss of myofibrils 7. The properties of the transgenic mice included: A. Increased ADH activity B. Increased body weight C. Decreased fertility D. Both A and C E. All of the above References Alexander, C. S., Electron microscopic observations in alcoholic heart disease. British heart journal '1967,' 29 (2), 200-6. Chen, D. B.; Wang, L.; Wang, P. H., Insulin-like growth factor I retards apoptotic signaling induced by ethanol in cardiomyocytes. Life Sciences '2000,' 67 (14), 1683-1693. Fernandez-Sola, J.; Preedy, V. R.; Lang, C. H.; Gonzalez-Reimers, E.; Arno, M.; Lin, J. C.; Wiseman, H.; Zhou, S.; Emery, P. W.; Nakahara, T.; Hashimoto, K.; Hirano, M.; Santolaria-Fernandez, F.; Gonzalez-Hernandez, T.; Fatjo, F.; Sacanella, E.; Estruch, R.; Nicolas, J. M.; Urbano-Marquez, A., Molecular and cellular events in alcohol-induced muscle disease. Department of Cardiology, First Clinical College of Harbin Medical University, Harbin, Heilongjiang, China. '2007,' 31 (12), 1953-62. Figueredo, V. M.; Chang, K. C.; Baker, A. J.; Camacho, S. A., Chronic alcohol-induced changes in cardiac contractility are not due to changes in the cytosolic Ca2+ transient. American Journal of Physiology - Heart and Circulatory Physiology '1998,' 275 (1), H122-H130. Hibbs, R. G.; Ferrans, V. J.; Black, W. C.; Weilbaecher, D. G.; Walsh, J. J.; Burch, G. E., Alcoholic cardiomyopathy. An electron microscopic study. American Heart Journal '1965,' 69 (6), 766-779. Hu, C.; Ge, F.; Hyodo, E.; Arai, K.; Iwata, S.; Lobdell, H. t.; Walewski, J. L.; Zhou, S.; Clugston, R. D.; Jiang, H.; Zizola, C. P.; Bharadwaj, K. G.; Blaner, W. S.; Homma, S.; Schulze, P. C.; Goldberg, I. J.; Berk, P. D., Chronic ethanol consumption increases cardiomyocyte fatty acid uptake and decreases ventricular contractile function in C57BL/6J mice. 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Postgraduate medical journal '1978,' 54 (633), 440-50. Olsen, E. G., Pathological recognition of cardiomyopathy. Postgraduate medical journal '1975,' 51 (595), 277-81. Piano, M. R., Alcoholic cardiomyopathy*: Incidence, clinical characteristics, and pathophysiology. CHEST Journal '2002,' 121 (5), 1638-1650. Regan, T. J.; Khan, M. I.; Ettinger, P. O.; Haider, B.; Lyons, M. M.; Oldewurtel, H. A.; Weber, M. Myocardial function and lipid metabolism in the chronic alcoholic animal. J. Clin. Invest. '''1974, 54'', 740. Richardson, P. J.; Wodak, A. D.; Atkinson, L.; Saunders, J. B.; Jewitt, D. E., Relation between alcohol intake, myocardial enzyme activity, and myocardial function in dilated cardiomyopathy. Evidence for the concept of alcohol induced heart muscle disease. British heart journal '1986,' 56 (2), 165-70. Sankaranarayanan, R. Clinical Review: Cardiomyopathy. http://www.gponline.com/Clinical/article/1031115/Clinical-Review-Cardiomyopathy (accessed 11/25, 2013). Schoppet, M.; Maisch, B., Alcohol and the Heart. Herz '2001,' 26 (5), 345-352. Urbano-Marquez, A.; Estruch, R.; Navarro-Lopez, F.; Grau, J. M.; Mont, L.; Rubin, E., The effects of alcoholism on skeletal and cardiac muscle. The New England journal of medicine '1989,' 320 (7), 409-15.Alexander, C. S., Electron microscopic observations in alcoholic heart disease. British heart journal '1967,' 29 (2), 200-6. Authors This wiki page was written by Daniel Liu, Jimmy Palakunnel, Christopher Sarro, Nicholas Savickas, Huasheng Wang for the purposes of the Biochemistry 3D03 Your Way Project. Latest activity Photos and videos are a great way to add visuals to your wiki. Find videos about your topic by exploring Wikia's Video Library. Category:Browse